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Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L.

Ramello MC, Tosello Boari J, Canale FP, Mena HA, Negrotto S, Gastman B, Gruppi A, Acosta Rodríguez EV, Montes CL - Cell Death Dis (2014)

Bottom Line: These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma.The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival.Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina.

ABSTRACT
Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors induce senescence of T cells, which are powerful suppressors of lympho-proliferation. In this study, we report that Tumor-Induced Senescent (TIS)-T cells may also modulate monocyte activation. To gain insight into this interaction, CD4+ or CD8+TIS-T or control-T cells were co-incubated with autologous monocytes under inflammatory conditions. After co-culture with CD4+ or CD8+TIS-T cells, CD14+ monocytes/macrophages (Mo/Ma) exhibit a higher expression of CD16+ cells and a reduced expression of CD206. These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma. TIS-T modulated-Mo/Ma show a higher production of pro-inflammatory cytokines (TNF, IL-1β and IL-6) and angiogenic factors (MMP-9, VEGF-A and IL-8) and a lower IL-10 and IP-10 secretion than monocytes co-cultured with controls. The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival. Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact. Although CD4+ shows different behavior from CD8+TIS-T cells, blocking mAbs against T-cell immunoglobulin and mucin protein 3 and CD40 ligand reduce pro-inflammatory cytokines and angiogenic factors production, indicating that these molecules are involved in monocyte/macrophage modulation by TIS-T cells. Our results revealed a novel role for TIS-T cells in human monocyte/macrophage modulation, which may have deleterious consequences for tumor progression. This modulation should be considered to best tailor the immunotherapy against cancer.

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Related in: MedlinePlus

Monocytes/macrophages modulation by CD4+ and CD8+ TIS-T cells requires cell-o-cell contact. Monocytes were co-cultured with CD4+ or CD8+ TIS-T cells in the same well (CoCulture, CC, gray bars) or cultured separately by a Transwell (TW, black bars), with stimulated CD4+ or CD8+ TIS-T cells in the insert and monocytes in the lower well. After 40 h of co-culture, LPS was added and 48 h later TNF, IL-1β, IL-6 and IL-8 were measured. Bars represent average of cytokine/angiogenic factor production±S.E.M. (n=3). Statistical analyses were performed using one-tailed paired t-test. P-values (CC versus TW) are indicated on each graph
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fig4: Monocytes/macrophages modulation by CD4+ and CD8+ TIS-T cells requires cell-o-cell contact. Monocytes were co-cultured with CD4+ or CD8+ TIS-T cells in the same well (CoCulture, CC, gray bars) or cultured separately by a Transwell (TW, black bars), with stimulated CD4+ or CD8+ TIS-T cells in the insert and monocytes in the lower well. After 40 h of co-culture, LPS was added and 48 h later TNF, IL-1β, IL-6 and IL-8 were measured. Bars represent average of cytokine/angiogenic factor production±S.E.M. (n=3). Statistical analyses were performed using one-tailed paired t-test. P-values (CC versus TW) are indicated on each graph

Mentions: To investigate whether Mo/Ma modulation mediated by TIS-T lymphocytes requires signals derived from cell contact or soluble factors, we performed TIS-T cell/Mo-Ma CCs as before and also in a transwell system (TW). The disruption of physical contact between monocytes and CD4+ or CD8+ TIS-T cells completely abrogated the ability of TIS-T cells to potentiate Mo/Ma production of TNF, IL-1β, IL-6 and IL-8 (Figure 4).


Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L.

Ramello MC, Tosello Boari J, Canale FP, Mena HA, Negrotto S, Gastman B, Gruppi A, Acosta Rodríguez EV, Montes CL - Cell Death Dis (2014)

Monocytes/macrophages modulation by CD4+ and CD8+ TIS-T cells requires cell-o-cell contact. Monocytes were co-cultured with CD4+ or CD8+ TIS-T cells in the same well (CoCulture, CC, gray bars) or cultured separately by a Transwell (TW, black bars), with stimulated CD4+ or CD8+ TIS-T cells in the insert and monocytes in the lower well. After 40 h of co-culture, LPS was added and 48 h later TNF, IL-1β, IL-6 and IL-8 were measured. Bars represent average of cytokine/angiogenic factor production±S.E.M. (n=3). Statistical analyses were performed using one-tailed paired t-test. P-values (CC versus TW) are indicated on each graph
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260722&req=5

fig4: Monocytes/macrophages modulation by CD4+ and CD8+ TIS-T cells requires cell-o-cell contact. Monocytes were co-cultured with CD4+ or CD8+ TIS-T cells in the same well (CoCulture, CC, gray bars) or cultured separately by a Transwell (TW, black bars), with stimulated CD4+ or CD8+ TIS-T cells in the insert and monocytes in the lower well. After 40 h of co-culture, LPS was added and 48 h later TNF, IL-1β, IL-6 and IL-8 were measured. Bars represent average of cytokine/angiogenic factor production±S.E.M. (n=3). Statistical analyses were performed using one-tailed paired t-test. P-values (CC versus TW) are indicated on each graph
Mentions: To investigate whether Mo/Ma modulation mediated by TIS-T lymphocytes requires signals derived from cell contact or soluble factors, we performed TIS-T cell/Mo-Ma CCs as before and also in a transwell system (TW). The disruption of physical contact between monocytes and CD4+ or CD8+ TIS-T cells completely abrogated the ability of TIS-T cells to potentiate Mo/Ma production of TNF, IL-1β, IL-6 and IL-8 (Figure 4).

Bottom Line: These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma.The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival.Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba, Argentina.

ABSTRACT
Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors induce senescence of T cells, which are powerful suppressors of lympho-proliferation. In this study, we report that Tumor-Induced Senescent (TIS)-T cells may also modulate monocyte activation. To gain insight into this interaction, CD4+ or CD8+TIS-T or control-T cells were co-incubated with autologous monocytes under inflammatory conditions. After co-culture with CD4+ or CD8+TIS-T cells, CD14+ monocytes/macrophages (Mo/Ma) exhibit a higher expression of CD16+ cells and a reduced expression of CD206. These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma. TIS-T modulated-Mo/Ma show a higher production of pro-inflammatory cytokines (TNF, IL-1β and IL-6) and angiogenic factors (MMP-9, VEGF-A and IL-8) and a lower IL-10 and IP-10 secretion than monocytes co-cultured with controls. The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival. Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact. Although CD4+ shows different behavior from CD8+TIS-T cells, blocking mAbs against T-cell immunoglobulin and mucin protein 3 and CD40 ligand reduce pro-inflammatory cytokines and angiogenic factors production, indicating that these molecules are involved in monocyte/macrophage modulation by TIS-T cells. Our results revealed a novel role for TIS-T cells in human monocyte/macrophage modulation, which may have deleterious consequences for tumor progression. This modulation should be considered to best tailor the immunotherapy against cancer.

Show MeSH
Related in: MedlinePlus